When control mechanism of gastrointestinal motility fails and prokinetic function is declined, atonic constipation and digestive symptoms such as abdominal distention, anorexia and heartburn emerge. Declined gastrointestinal motility is found with aging, stress or diseases such as chronic gastritis, non-ulcer dyspepsia, reflux esophagitis, peptic ulcer, diabetes and the like, and gastrointestinal prokinetic agents have been used for treatment.
Ever since metoclopramide (The Merck Index, vol. 11, 6063) was developed as a gastrointestinal prokinetic agent, various substituted benzamide derivatives have been synthesized. At present, cisapride (The Merck Index, vol. 11, 2318) and others have been clinically used as gastrointestinal prokinetic agents besides metoclopramide. While benzamide derivatives such as metoclopramide and cisapride have been speculated to show effects via certain receptors in the digestive organs, the actual function of the receptors involved in the promotion of gastrointestinal motility has long been unclarified. Recently, however, 5-HT.sub.4 receptor has been identified to be a new serotonin receptor subtype which stimulates adenylate cyclase activity, and benzamide derivatives have been found to promote gastrointestinal motility by activating 5-HT.sub.4 receptor in the digestive organs The Journal of Pharmacology and Experimental Therapeutics, vol. 252, pp. 1378-1386 (1990), European Journal of Pharmacology, vol. 196, pp. 149-155 (1991)!. Having found the action of metoclopramide and cisapride as 5-HT.sub.4 receptor agonists, many attempts have been made to use 5-HT.sub.4 receptor agonists as gastrointestinal prokinetic agents. The Journal of Pharmacology and Experimental Therapeutics, vol. 264, pp. 240-248 (1993) reports that substituted benzamide (SC53116) which is a 5-HT.sub.4 receptor agonist stimulated gastrointestinal motility. As 5-HT.sub.4 receptor agonists, Japanese Patent Unexamined Publication No. 157518/1994 discloses oxadiazole derivatives; Japanese Patent Unexamined Publication No. 10881/1995 discloses oxazabicyclo derivatives; and WO 94/12497 discloses endo-N-(8-methyl-8-azabicyclo3.2.1!oct-3-yl)-1-isopropyl-2(1 H)-quinolone-3-carboxamide and acid addition salts thereof.
The 5-HT.sub.4 receptor has been found to be also present in brain (e.g., prefrontal area, nigra, hippocampus and amygdaloid complex), heart, endocrine system and urinary system British Journal of Pharmacology, vol. 109, pp. 618-624 and Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 344, pp. 150-159, Trends in Pharmacological sciences, vol. 13, pp. 141-145 (1992), Pharmacological Reviews, vol. 46, pp. 182-185 (1994)!.
In addition, since activation of 5-HT.sub.4 receptor in the central nervous system promotes release of acetylcholine in prefrontal area, 5-HT.sub.4 receptor is responsible for memory and learning mechanism through release of acetylcholine. Therefore, a 5-HT.sub.4 agonist has a potential for a drug for the prophylaxis and treatment of disturbance of memory, dementia and the like. In view of a report documenting that 5-HT.sub.4 receptor on GABA neuron is involved in anxiety, it also has a potential for a drug for the prophylaxis and treatment of anxiety. Furthermore, the action of 5-HT.sub.4 receptor on heart and urinary system has been reported Trends in Pharmacological Sciences, vol. 16, pp. 391-398 (1995)!.
In view of such disclosures, a compound having affinity for 5-HT.sub.4 receptor is considered to be clinically applicable to digestive organs, brain, heart and urinary system. In other words, a 5-HT.sub.4 receptor agonist should be useful as a medication for the prophylaxis and treatment of various gastrointestinal diseases (e.g., reflux esophagitis; gastroesophageal reflux such as that accompanying cystic fibrosis; Barrett syndrome; intestinal pseudoileus; acute or chronic gastritis; gastric or duodenal ulcer; Crohn's disease; non-ulcer dyspepsia; ulcerative colitis; postgastrectomy syndrome; postoperative digestive function failure; delayed gastric emptying caused by gastric neurosis, gastroptosis, diabetes, and the like; gastrointestinal disorders such as indigestion, meteorism, abdominal indefinite complaint, and the like; constipation such as atonic constipation, chronic constipation, and that caused by spinal cord injury, pelvic diaphragm failure and the like; and irritable bowel syndrome), central nervous disorders (e.g., schizophrenia, depression, anxiety, disturbance of memory and dementia), cardiac function disorders (e.g., cardiac failure and myocardial ischemia), urinary diseases (e.g., dysuria caused by urinary obstruction, ureterolith, prostatomegaly, spinal cord injury, pelvic diaphragm failure, etc.) and the like.
In addition, a report has documented that 5-HT.sub.4 receptor antagonist shows an antagonistic action on analgesic action of cisapride and metoclopramide Arzneimittel Forschung,-vol. 43, pp. 913-918 (1993)!. Thus, a 5-HT.sub.4 receptor agonist is expected to be useful as an anti-nociceptor for analgesic use which increases threshold of pain.
While there have been documented some compounds which selectively activate 5-HT.sub.4 receptors Journal of Medicinal Chemistry, vol. 35, pp. 1486-1489 (1992)!, a compound has not been known at all, which has, at an alkyl moiety bound to nitrogen atom of cyclic amine, amide, urea, amino, (thio)ether, (thio)carbonyl, sulfinyl, sulfonyl or a heterocycle having amide or urea bonding in the ring.
The above-mentioned substituted benzamide derivatives, such as metoclopramide, have, besides 5-HT.sub.4 receptor agonistic effect, dopamine 2 (hereinafter referred to as D.sub.2) receptor antagonism or serotonin 3 (hereinafter referred to as 5-HT.sub.3) receptor antagonism, and are not entirely satisfactory in terms of efficacy and safety, since they cause side effects such as extrapyramidal disorders due to D.sub.2 receptor antagonism, and side effects such as constipation due to 5-HT.sub.3 receptor antagonism Drugs, vol. 41, pp. 574-595 (1991)!, and are associated with such problems to be solved.
As gastrointestinal prokinetic agents, Japanese Patent Unexamined Publication Nos. 262724/1993, 50883/1989 and 211685/1992 disclose compounds having 5-HT.sub.3 receptor antagonism. These compounds again cause side effects such as constipation, as mentioned above, and are not satisfactory. Since 5-HT.sub.4 receptors are reportedly distributed widely in the entirety of digestive organs, a 5-HT.sub.4 receptor agonist which shows low affinity for D.sub.2 receptor and 5-HT.sub.3 receptor, but shows high and selective affinity for 5-HT.sub.4 receptors and activate same is expected to make a superior gastrointestinal prokinetic agent.
Accordingly, the present invention aims at providing a compound having high and selective affinity for 5-HT.sub.4 receptors and capable of activating same in various tissues, which is useful as a medication for the prophylaxis and treatment of various gastrointestinal diseases (e.g., reflux esophagitis; gastroesophageal reflux such as that accompanying cystic fibrosis; Barrett syndrome; intestinal pseudoileus; acute or chronic gastritis; gastric or duodenal ulcer; Crohn's disease; non-ulcer dyspepsia; ulcerative colitis; postgastrectomy syndrome; postoperative digestive function failure; delayed gastric emptying caused by gastric neurosis, gastroptosis, diabetes, and the like; gastrointestinal disorders such as indigestion, meteorism, abdominal indefinite complaint, and the like; constipation such as atonic constipation, chronic constipation, and that caused by spinal cord injury, pelvic diaphragm failure and the like; and irritable bowel syndrome), central nervous disorders (e.g., schizophrenia, depression, anxiety, disturbance of memory and dementia), cardiac function disorders (e.g., cardiac failure and myocardial ischemia), urinary diseases (e.g., dysuria caused by urinary obstruction, ureterolith, prostatomegaly, spinal cord injury, pelvic diaphragm failure, etc.), and the like, and also useful as an anti-nociceptor for analgesic use which increases threshold of pain.
According to the present invention, there has now been found a new benzoic acid compound, namely, a benzoic acid compound having, at an alkyl moiety bound to nitrogen atom of cyclic amine of the following formulas (II-a)-(II-f) and (III), amide, urea, amino, (thio)ether, (thio)carbonyl, sulfinyl, sulfonyl or a heterocycle having amide or urea bonding in the ring, which shows superior selective activation of 5-HT.sub.4 receptors.